Abstract

The function of exhausted CD8 T cells in chronic HIV-1 infection is negatively regulated by the PD-L1/PD-1 pathway resulting in suppression of specific anti-viral T cell responses. Blockade of this pathway reconstitutes T cell function and enhances antiviral immune responses. In HIV-infected individuals, increased PD-L1 (B7-H1) expression on APCs correlates directly with viral load, indicating a potential effect of the virus on PD-L1 expression. However, the mechanisms of PD-L1 up-regulation in these settings are not well understood. In this study, we investigated how PD-L1 expression is regulated in human pDCs. We found PD-L1 expression on pDC was up-regulated with different viral stimulations including HSV, Sendai virus, Influenza virus and both live and AT-2 inactivated HIVMN. PD-L1 levels were differentially regulated by stimulation with different viruses. In comparison with these virus stimulations, TLR9 ligands CpGA and-B were less efficient at inducing PD-L1 expression. TNF-α and IL-6 had no influence on PD-L1 although IFN-α had a moderate effect on it, indicating that up-regulation of PD-L1 on pDC was specifically a primary response to viral stimulation. Furthermore, we observed that LPS enhanced virus-induced PD-L1 expression on pDC, suggesting potential involvement of LPS in the up-regulation of PD-L1 in chronic HIV-1 infection. Taken together, our results suggest a potential role for up-regulation of PD-L1 expression on pDC in HIV-induced immune exhaustion.